EXPERIMENTAL STUDY
Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy
Antonio Rapacciuolo, MD*,
Giovanni Esposito, MD*,
Kathleen Caron, PhD ,
Lan Mao, MD*,
Steven A. Thomas, MD, PhD and
Howard A. Rockman, MD*
* Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Manuscript received January 23, 2001;
revised manuscript received May 1, 2001,
accepted May 21, 2001.
Reprint requests and correspondence: Dr. Howard A. Rockman, Department of Medicine, Duke University Medical Center, DUMC 3104, Durham, North Carolina 27710
h.rockman{at}duke.edu
OBJECTIVES
We sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways.
BACKGROUND
Cardiac hypertrophy is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Although considerable evidence suggests that G-protein–coupled receptors are involved in the hypertrophic response, it remains controversial whether catecholamines are required for the development of in vivo cardiac hypertrophy.
METHODS
We performed transverse aortic constriction (TAC) in dopamine beta-hydroxylase knockout mice (Dbh–/–, genetically altered mice that are completely devoid of endogenous norepinephrine and epinephrine) and littermate control mice. After induction of cardiac hypertrophy, the mitogen-activated protein kinase (MAPK) signaling pathways were measured in pressure-overloaded/wild-type and Dbh–/– hearts.
RESULTS
Compared with the control animals, cardiac hypertrophy was significantly blunted in Dbh–/– mice, which was not associated with altered cardiac function, as assessed by transthoracic echocardiography in conscious mice. The extracellularly regulated kinase (ERK 1/2), c-jun–NH2-terminal kinase (JNK) and p38 MAPK pathways were all activated by two- to threefold after TAC in the control animals. In contrast, induction of the three pathways (ERK 1/2, JNK and p38) was completely abolished in Dbh–/– mice.
CONCLUSIONS
These data demonstrate a nearly complete requirement of endogenous norepinephrine and epinephrine for the induction of in vivo pressure-overload cardiac hypertrophy and for the activation of hypertrophic signaling pathways.
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Abbreviations and Acronyms
| | AR | = adrenergic receptor | | BW | = body weight | | Dbh–/– | = dopamine beta-hydroxylase knockout mice | | ERK | = extracellularly regulated kinase | | %FS | = percent fractional shortening | | JNK | = c-jun–NH2-terminal kinase | | L-DOPS | = L-threo-3,4-dihydroxyphenylserine | | LV | = left ventricular | | LVW | = left ventricular weight | | MAPK | = mitogen-activated protein kinase | | TAC | = transverse aortic constriction | | TL | = tibial length |
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